3rd EurocanPlatform Translational Research Course

Prediction of side-effects of anti-cancer drugs

Dr Gerard Milano - Centre Antoine Lacassagne, Nice, France

I was supposed to talk about prediction of toxicity in cancer management so my talk was dedicated to two applications, pharmacokinetics and pharmacogenetics. In terms of pharmacokinetics it is the most famous way to predict toxicity just because we are able to identify some blood levels which are linked to the risk of toxicity. In terms of pharmacogenetics it’s a bit different, we are able to characterise some polymorphisms, some genetic polymorphisms, in individuals which favour the occurrence of toxicity.

What significance does this have for clinical practice?

There are a lot of impacts, potential impacts, especially in terms of prediction of risk of toxicity for fluoropyrimidines. Fluoropyrimidines, or 5-FU, are the main drugs which are still used in cancer management, for instance colorectal cancer, breast cancer, head and neck cancer. More and more fluoropyrimidines are given by oral route as the main drug is capecitabine, Xeloda. There is a big concern about the prediction of risk of toxicity for these drugs and mainly an enzyme which is named dihydropyrimidine dehydrogenase, DPD, for which deficiencies are linked to the risk to develop serious toxicity. So the challenge is how to detect patients, subjects at risk of DPD deficiency.

What are the next steps for this work?

The next step would be to generalise the test, point of care test, a very fashionable term, which would be able to screen general populations of patients for the risk to have DPD deficiency. We are applying for a European grant for this kind of test.

What are the challenges facing this work?

The main problem is technical difficulties to develop such a test because we need very specific monoclonal antibodies able to determine some compounds which are generated by this enzyme. If we have not specific monoclonal antibodies for this kind of test then the quality of the test will be not good and we cannot support the development of this test.

What will be the benefit of this work?

The benefit is potentially huge. So because toxicity to fluoropyrimidines are frequent, something around 5-10%, the consequence of toxic events with fluoropyrimidine are very event in terms of duration of hospitalisation, delay for treatment, so in terms of hospital costs. So it is absolutely necessary to have in hand the test which could prevent this kind of problem.

What is your take home message?

Take courage for the cancer fight so we have tools to help you, not only in terms of new drugs but new means to improve treatment outcomes.